Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). These studies tend to be very long term with varying activity. Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues; in collaboration with an international consortium (GenoMEL), a search for a new melanoma susceptibility genes continues both within families and a genome-wide association study. In a methodologic study, we compared CDKN2A mutation detection using denaturing high performance liquid chromatography to usual screening acorss nine different centers in GenoMEL. We found that mutation detection across the groups was consistent and of high quality. We continue to accrue and evaluate new families. Genome-wide linkage analyses of 51 Italian melanoma families from the Emilio Romagna area without CDKN2a or CDK4 mutations have found no significant evidence of linkage. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. With these additional families, linkage analyses showed evidence of linkage in a different chromosomal area. Sequencing of candidate genes in the both identified linkage intervals continues. Studying families with lymphoproliferative cancers has been a long-standing interest. In a collaboration between two consrotia, we have conducted a linkage analysis on 206 CLL kindreds which identified several areas of interest for further study. We obtained a maximal nonparametric linkage (NPL) score of 3.02 (p=0.001) on chromosome 2q21.2. The same area also showed the highest multipoint hetergeneity LOD score uncer a common recessive modal of susceptibilit (HLOD = 3.11; p less than 0.0001). Two other areas 6p22.1 (HLA region) and 18q21.1 had HLOD scores above 2. We have continued working with the Urologic Oncology Branch in the evaluation of families with renal cancers. In families with fumarate hydratase mutations with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) in North America, we evaluated the risk factors for uterine leiomyomas. Women in these families had high rates of hysterectomy before age 30 for multiple uterine leiomyomas. Risk of developing leiomyomas was much higher in individuals either clinically affected with HLRCC or with mutations in FH. We also continued a family study of Xeroderma pigmentosum in collaboration with CCR investigators to assess risk of cancer in XP heterozygotes. Data collection is underway. We have also documented that mothers carrying affected children with tricothiodystrophy have more pregnancy complications than when carrying unaffected children.